Indicated for the management of mild to moderate pain where treatment with an opioid is appropriate and for which alternative treatments are inadequate.

Because of the risks of addiction, abuse, and misuse, with opioids, even at recommended doses, reserve TYLENOL with Codeine for use in patients for whom alternative treatment options [e.g., non-opioid analgesics], have not provided adequate analgesia, or are not expected to provide adequate analgesia, and have not been tolerated, or are not expected to be tolerated.

To ensure that the benefits of opioid analgesics outweigh the risks of addiction, abuse, and misuse, the Food and Drug Administration (FDA) has required a REMS for these products.

TYLENOL #3 has 30 mg of codeine and 300 mg of acetaminophen, TYLENOL #4 has 60 mg of codeine and 300 mg of acetaminophen.

TYLENOL with Codeine should not be abruptly discontinued.

TYLENOL with Codeine exposes patients and other users to the risks of opioid addiction, abuse and misuse, which can lead to overdose and death. Assess each patient’s risk prior to prescribing TYLENOL with Codeine, and monitor all patients regularly for the development of these behaviors and conditions.

Serious, life-threatening, or fatal respiratory depression may occur with use of TYLENOL with Codeine.  While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of TYLENOL with Codeine, the risk is greatest during the initiation of therapy or following a dosage increase. Monitor patients closely for respiratory depression, especially within the first 24-72 hours of initiating therapy with and following dosage increases of TYLENOL with Codeine.

Opioids can cause sleep-related breathing disorders including central sleep apnea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the opioid dosage using best practices for opioid taper.

Life-threatening respiratory depression and death have occurred in children who received codeine. Based upon post-marketing reports, children younger than 12 years of age appear to be more susceptible to the respiratory depressant effects of codeine, particularly if there are risk factors for respiratory depression. For example, many reported cases of death occurred in the post-operative period following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being ultra-rapid metabolizers of codeine. Furthermore, children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to its respiratory depressant effects.

Because of the risk of life-threatening respiratory depression and death TYLENOL with Codeine tablets are contraindicated for all children younger than 12 years of age.

TYLENOL with Codeine tablets are contraindicated for post-operative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy.

Avoid the use of TYLENOL with Codeine tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine unless the benefits outweigh the risks. Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.

Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (e.g., gene duplications denoted as *1/*1xN or *1/*2xN). These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. Therefore, individuals who are ultra-rapid metabolizers should not use TYLENOL with Codeine tablets.

Acetaminophen has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of acetaminophen at doses that exceed 4,000 milligrams per day, and often involve more than one acetaminophen-containing product.

Instruct patients to look for acetaminophen or APAP on package labels and not to use more than one product that contains acetaminophen. Instruct patients to seek medical attention immediately upon ingestion of more than 4,000 milligrams of acetaminophen per day, even if they feel well.

Cases of adrenal insufficiency have been reported with opioid use, more often following greater than 1 month of use. Presentation of adrenal insufficiency may include non-specific symptoms and signs including nausea, vomiting, anorexia, fatigue, weakness, dizziness, and low blood pressure.

Rarely, acetaminophen may cause serious skin reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson Syndrome (SJS), and toxic epidermal necrolysis (TEN), which can be fatal.

In patients who may be susceptible to the intracranial effects of CO2 retention (e.g., those with evidence of increased intracranial pressure or brain tumors), TYLENOL with Codeine may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Monitor such patients for signs of sedation and respiratory depression, particularly when initiating therapy with TYLENOL with Codeine.

Opioids may also obscure the clinical course in a patient with a head injury. Avoid the use of TYLENOL with Codeine in patients with impaired consciousness or coma.

The codeine in TYLENOL with Codeine may increase the frequency of seizures in patients with seizure disorders, and may increase the risk of seizures occurring in other clinical settings associated with seizures.

Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients because they may have altered pharmacokinetics, including clearance, compared to younger, healthier patients.

TYLENOL with Codeine may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics.

TYLENOL with Codeine tablets may impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of TYLENOL with Codeine tablets and know how they will react to the medication.

TYLENOL with Codeine is contraindicated for:

• All children younger than 12 years of age
• Post-operative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy
• Patients with significant respiratory depression
• Patients with acute or severe bronchial asthma in an unmonitored setting or in the absence of resuscitative equipment
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs within the last 14 days
• Known or suspected gastrointestinal obstruction, including paralytic ileus

The concomitant use of TYLENOL with Codeine with all CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir) or discontinuation of a CYP3A4 inducer such as rifampin, carbamazepine, and phenytoin, may result in an increase in codeine plasma concentrations with subsequently greater metabolism by CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression.

The concomitant use of TYLENOL with Codeine tablets and CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin) can result in lower codeine levels, greater norcodeine levels, and less metabolism via CYP2D6 with resultant lower morphine levels, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.

The concomitant use of TYLENOL with Codeine with all CYP2D6 inhibitors (e.g., amiodarone, quinidine) may result in an increase in codeine plasma concentrations and a decrease in active metabolite morphine plasma concentration which could result in an analgesic efficacy reduction or symptoms of opioid withdrawal.

Profound sedation, respiratory depression, coma, and death may result from the concomitant use of TYLENOL with Codeine tablets with benzodiazepines and/or other CNS depressants (e.g., non-benzodiazepine sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol). Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate.

The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. Examples of these drugs include, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), and monoamine oxidase (MAO) inhibitors (used to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).

The concomitant use of opioids and MAOIs, such as phenelzine, tranylcypromine, linezolid, may manifest as serotonin syndrome or opioid toxicity. Advise patients taking TYLENOL with Codeine not to use MAOIs or within 14 days of stopping such treatment.

TYLENOL with Codeine tablets may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Avoid the concomitant use of opioids with other opioid analgesics, such as butorphanol, nalbuphine, pentazocine, may reduce the analgesic effect of TYLENOL with Codeine and/or precipitate withdrawal symptoms.

Avoid the use of mixed agonist/antagonist (e.g, pentazocine, nalbuphine, and butorphanol) or partial agonist (e.g., buprenorphine) analgesics in patients who are receiving a full opioid agonist analgesic, including TYLENOL with Codeine.

Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.

The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Codeine may increase serum amylase levels.

Acetaminophen may produce false-positive test results for urinary 5-hydroxyindoleacetic acid.

Inform patients that chronic use of opioids may cause reduced fertility. It is not known whether these effects on fertility are reversible.

Prolonged use of TYLENOL with Codeine during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.

At least one death was reported in a nursing infant who was exposed to high levels of morphine in breast milk because the mother was an ultra-rapid metabolizer of codeine. Breastfeeding is not recommended during treatment with TYLENOL with Codeine tablets.

GoToSource

• Adult dosage of codeine phosphate greater than 360 mg in a 24 hour time period and acetaminophen dosage greater than 4,000 mg in a 24 hour time period. GoToSource

• Post-operative pain management in patients under the age of 18 undergoing tonsillectomy and/or adenoidectomy. GoToSource

Erythromycin/codeine-induced psychotic mania. GoToSource 

Postoperative deaths in children with obstructive sleep apnea who received codeine for pain relief following a tonsillectomy and/or adenoidectomy. GoToSource

Neonatal withdrawal syndrome. GoToSource

Stevens-johnson syndrome, toxic epidermal necrolysis and acute generalized exanthematous pustulosis. GoToSource

Abuse and dependence. GoToSource

Adrenal insufficiency. GoToSource

Sedation, respiratory depression, mental clouding, euphoria, agitation and constipation. GoToSource

Serotonin syndrome, decreased sex hormone levels including reduced interest in sex, impotence or infertility. GoToSource

Pancreatitis. GoToSource

Liver failure and anaphylaxis. GoToSource

Lawsuits filed for liver failure.